PROJECT SUMMARY Avanti Biosciences? mission is to develop effective therapeutics for Alzheimer?s disease (AD). Recent scientific discoveries have identified hyperphosphorylated tau as toxic culprits in disease progression leading to the formation of neurofibrillary tangles (NFTs), one of the main hallmark of the disease. The kinase DYRK1A has been shown to have a direct role in the phosphorylation of tau. Increased DYRK1A immunoreactivity has been reported in the cytoplasm and nuclei of scattered neurons of the entorhinal cortex, hippocampus and neocortex in neurodegenerative diseases associated with tau phosphorylation, including Alzheimer?s disease. DYRK1A induced phosphorylation of tau reduces the biological activity of tau protein and promotes tau self-aggregation and fibrillization. The abnormal tau phosphorylation causes the loss of tau biological function, resulting in reduced activity to stimulate microtubule assembly. Neurofibrillary degeneration is the leading cause of neuronal death and dementia in DS?AD and AD. The involvement of DYRK1A in neurofibrillary degeneration indicates that therapeutic inhibition of DYRK1A activity are hypothesized to be disease-modifying treatments that would be effective throughout the course of the disease, and significantly impact the lives of the millions of Alzheimer?s patients. Pharmaceutical industry efforts targeted specifically at modulation of DYRK1A are currently limited. Avanti Biosciences is one of the only companies uniquely focused on discovery of small molecule DYRK1A modulator derived from natural catechins. It has been reported that the main ingredient of green tea, epigallocatechin gallate (EGCG) is a potent allosteric inhibitor of DYRK1A. In an effort to discover new derivatives that exert the same activity and improved drug-like properties we have screened the various component of green tea. With our surprise, EGCG was not the most potent catechin in the mixture. The trans catechin derivatives Gallocatechin gallate (GCG) and Catechin gallate (GC) showed improved activity combined with an increased chemical stability. During the first phase of the grant we have discovered that CG has much improved ADME properties compared to EGCG and using our proprietary intranasal formulation we are now able to reach the brain in therapeutic concentrations. We were also able to demonstrate that our lead compound unequivocally can engage the target at both enzymatic and cellular levels and to reduce the phosphorylation of tau which has been shown to be relevant in the AD progression. The project is now ready to enter into Phase 2 were we will further evaluate our lead compound in the animal model and looking in more detail at safety studies. Avanti Biosciences is requesting an administrative supplement to meet increased costs that are within the scope of the approved award but were unforeseen when the application was submitted. This supplement focuses on the development of an intranasal formulation to be used during Phase 2 of the grant in our efficacy and safety animal studies.